Imidazopyridine derivatives for the treatment of hypertension

ABSTRACT

An imidazopyridine derivative is disclosed of the formula [I]: ##STR1## wherein R 1  is lower alkyl, R 2  is hydrogen, lower alkylsulfonyl or a group of the formula ##STR2## where Z is oxygen or two hydrogen atoms, R 0  is lower alkyl, lower alkoxy, phenyl, hydrogen, di(lower alkyl) amino or lower alkenyl, R 3  is carboxyl or lower alkoxycarbonyl and Ring A is substituted phenyl, and pharmaceutically acceptable salts thereof that are useful in prophylaxis and treatment of hypertension.

This application is a divisional of copending application Ser. No.07/940,336, filed on Sep. 3, 1992, the entire contents of which arehereby incorporated by reference.

The present invention relates to novel imidazopyridine derivativeshaving a hypotensive activity, and processes for preparation thereof.

PRIOR ART

Angiotensin II is a biologically active peptide consisting of eightamino acids, which is produced by specific conversion of angiotensin Iby an angiotensin converting enzyme during circulation mainly in thelung. Said angiotensin II constricts vascular smooth muscle as well aspromotes the secretion of aldosterone in the adrenal cortex, by whichangiotensin II increases blood pressure. Therefore, it is well knownthat angiotensin II receptor antagonists may be useful in the treatmentof hypertension.

Based on the above-mentioned mechanism of action, there have been knownsome hypotensive agents, for example,2-n-butyl-4-chloro-5-hydroxymethyl-1-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]imidazole,and the like (cf. European Patent Publication No. 253310A), but theseconventional hypotensive agents are all the compounds having amonocyclic nucleus, i.e. imidazole nucleus.

BRIEF DESCRIPTION OF THE INVENTION

An object of the present invention is to provide novel condensedring-type imidazopyridine derivatives and pharmaceutically acceptablesalts thereof, which show potent angiotensin II inhibitory activitiesand are useful as a hypotensive agent. Another object of the inventionis to provide processes for preparing the said imidazopyridinederivatives.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to imidazopyridine derivatives of thefollowing formula [I], and pharmaceutically acceptable salts thereof,and further relates to processes for preparing the same. ##STR3##wherein R¹ is hydrogen atom or a lower alkyl group; R² is hydrogen atom,a lower alkylsulfonyl group or a group of the formula: ##STR4## in whichZ is oxygen atom or two hydrogen atoms, and R⁰ is i) a substituted orunsubstituted lower alkyl group, ii) a lower alkoxy group, iii) a 5- or6-membered heteromonocyclic group, iv) a substituted or unsubstitutedphenyl group, v) hydrogen atom, vi) a substituted or unsubstituted aminogroup, or vii) a lower alkenyl group; R³ is carboxyl group or a loweralkoxycarbonyl group; and Ring A is a substituted or unsubstitutedphenyl group.

Preferred examples of the present compounds [I]are compounds of theformula [I], wherein R⁰ is i) a lower alkyl group which may optionallybe substituted by 1 to 2 groups selected from phenyl group, ahalogenophenyl group, carboxyl group, a lower alkoxycarbonyl group,cyano group, benzyloxycarbonyl group, a lower alkylthio group, a loweralkylcarbonylamino group, benzoyl group, and a lower alkylcarbonylgroup, ii) a lower alkoxy group, iii) a 5- or 6-membered heterocyclicgroup selected from pyridyl group, furyl group and thienyl group, iv)phenyl group, v) hydrogen atom, vi) a di(lower alkyl)amino group or vii)a lower alkenyl group, and Ring A is a phenyl group substituted by agroup selected from a protected or unprotected tetrazolyl group,carboxyl group and a lower alkoxycarbonyl group.

When Ring A is a protected tetrazotyl-substituted phenyl ring, aprotecting group for tetrazolyl group includes, for example, tritylgroup, a tri-lower alkylsilyl group, a cyano-lower alkyl group, a loweralkoxybenzyl group, and the like.

Preferred compounds [I] in view of their excellent pharmacologicalactivity are compounds of the formula [I] wherein R¹ is a lower alkylgroup; R² is hydrogen atom, a lower alkylcarbonyl group, a carboxy-loweralkylcarbonyl group, a phenylcarbonyl group or thienylcarbonyl group; R³is carboxyl group or a lower alkoxycarbonyl group; and Ring A is aphenyl group substituted by a group selected from tetrazolyl group,carboxyl group and a lower alkoxycarbonyl group.

More preferred compounds as a medicament are compounds of the formula[I] wherein R¹ is a lower alkyl group; R² is a lower alkylcarbonylgroup; R³ is carboxyl group; and Ring A is a tetrazolyl-substitutedphenyl group.

The compounds [I] of the present invention may be used as a medicamenteither in the form of a free base or a pharmaceutically acceptable saltthereof. The pharmaceutically acceptable salts are, for example, alkalimetal salts (e.g. sodium salt, potassium salt, etc.), alkaline earthmetal salts (e.g. calcium salt, magnesium salt, etc.), heavy metal salts(e.g. zinc salt, etc.), and organic amine salts (e.g. ammonium salt,triethylamine salt, pyridine salt, ethanolamine salt, a basic amino acidsalt, etc.). These salts may easily be prepared by treating thecompounds [I] with the corresponding inorganic or organic base in anappropriate solvent.

The compounds [I] of the present invention may exist in the form of twooptically active isomers due to an asymmetric carbon atom thereof, andthe present invention also includes these optically active isomers and amixture thereof.

The compounds [I] of the present invention and pharmaceuticallyacceptable salts thereof may be administered either orally orparenterally and may also be used in the form of a pharmaceuticalpreparation in admixture with pharmaceutically acceptable excipientssuitable for oral administration or parenteral administration. Thepharmaceutical preparations may be in solid form such as tablets,capsules, powders, etc., or in liquid form such as solutions,suspensions, emulsions, and the like. When administered parenterally, itmay be used in the form of an injection preparation.

The daily dose of the compounds [I] of the present invention andpharmaceutically acceptable salts thereof varies depending on age,weight, conditions of patients and severity of diseases, but whenadministered orally, it is usually in the range of 0.01 to 10 mg/kg,preferably 0.03 to 5 mg/kg, and when administered parenterally, it isusually in the range of 0.002 to 1 mg/kg, preferably 0.01 to 0.3 mg/kg.

According to the present invention, the compounds [I] can be prepared byreacting a compound of the formula [II]: ##STR5## wherein the symbolsare the same as defined above, or a salt thereof with a compound of theformula [III]: ##STR6## wherein X¹ is a reactive residue, and Ring A isthe same as defined above, or a salt thereof.

Among the compounds [I] of the present invention, the compound of theformula [I-a]: ##STR7## wherein the symbols are the same as definedabove, can be prepared by reacting a compound of the formula [IV]:##STR8## wherein the symbols are the same as defined above, or a saltthereof, with a compound of the formula [V]:

    R.sup.3 --CHO                                              [V]

wherein R³ is the same as defined above, or a salt thereof.

Moreover, the compound of the formula [I-b]: ##STR9## wherein R²¹ is alower alkylsulfonyl group or a group of the formula: ##STR10## in whichZ is oxygen atom or two hydrogen atoms, and R⁰ is i) a substituted orunsubstituted lower alkyl group, ii) a lower alkoxy group, iii) a 5- or6-membered heteromonocyclic group, iv) a substituted or unsubstitutedphenyl group, v) hydrogen atom, vi) a substituted or unsubstituted aminogroup or vii) a lower alkenyl group, and the other symbols are the sameas defined above, can be prepared by reacting the compound [I-a] or asalt thereof with a compound [VI]:

    X.sup.2 --R.sup.21                                         [VI]

wherein X² is hydroxyl group, and R²¹ is the same as defined above, asalt or a reactive residue thereof.

The reaction between the compound [II] and the compound [III] is carriedout in the presence of an alkali metal hydride or an alkali metalalkoxide, or in the presence of an acid acceptor. Suitable examples ofthe reactive residue (X¹) of the compound [III] are, for example,halogen atoms, and the like.

When the reaction is carried out in the presence of an alkali metalhydride or an alkali metal alkoxide, the alkali metal hydride includes,for example, sodium hydride, potassium hydride, etc., and the alkalimetal alkoxide includes, for example, sodium methoxide, sodium ethoxide,potassium t-butoxide, and the like. The reaction is preferably carriedout in a suitable solvent, under cooling or heating, for example, at atemperature of -30° C. to 50° C., more preferably at a temperature of-10° C. to room temperature. The solvent includes, for example, adi-lower alkylformamide, a di-lower alkylsulfoxide, a di-loweralkylacetamide, a lower alkanol, and the like.

When the reaction is carried out in a presence of an acid acceptor, theacid acceptor includes, for example, alkali metal carbonates, and thelike. The reaction is carried out in a suitable solvent under cooling orheating, for example, at a temperature of -10° C. to 100° C. The solventincludes, for example, acetone, dimethylformamide, dimethylsulfoxide,and the like.

In the reaction, the compounds [I] may be obtained in the form of amixture of two position isomers, which are produced by reacting thecompound [II] with the compound [III] at the 1- or 3-position of theimidazopyridine ring of the compound [II]. In this case, the obtainedcompounds [I] in the form of a mixture of the position isomers can beseparated by a conventional manner such as silica gel columnchromatography and recrystallization.

The reaction between the compound [IV] and the compound [V] can becarried out in the presence or absence of an acid or a base. The acidincludes, for example, inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid, etc., and the base includes, forexample, inorganic bases such as alkali metal hydroxides, alkali metalcarbonates, alkali metal hydrogen carbonates, and the like. The reactionis carried out in a suitable solvent under cooling or heating, forexample, at a temperature of 10° C. to 100° C., preferably at atemperature from room temperature to a boiling point of the solvent tobe used. The solvent includes, for example, water, lower alcohols, ortetrahydrofuran, dioxane, or a mixture of water and one of these othersolvents.

The reaction between the compound [I-a] and the compound [VI] can becarried out in a conventional manner. For example, the reaction iscarried out in the presence of a base or a condensing agent. In thereaction, the compound [VI] may also be used in the form of an acidanhydride thereof, or a reactive derivative thereof, that is, X² of thecompound [VI] is a halogen atom, and the like. Moreover, when R²¹ of thecompound [VI] is acetoacetyl, the compound [VII ] may be in the form ofan anhydride thereof, i.e. diketene.

When the reaction is carried out in the presence of a base, the base maybe any conventional ones, and preferably includes, for example, organicbases such as tri-lower alkylamine, pyridine, 4-di-loweralkylaminopyridine, and the like, or inorganic bases such as alkalimetal hydrogen carbonates, alkali metal carbonates, alkali metalhydroxides, and the like. The reaction is carried out in a suitablesolvent under cooling of heating, for example, at a temperature of -30°C. to 100° C., preferably at a temperature of -10° C. to a boiling pointof the solvent to be used. The solvent includes, for example, methylenechloride, chloroform, ethyl acetate, tetrahydrofuran, ether, or amixture of one of these solvents and water.

When the reaction is carried out in the presence of a condensing agent,the condensing agent includes, for example, dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,and the like. In addition, a compound such as hydroxybenzotriazole,N-hydroxysuccinimide, etc., may be used as a promoter. The reaction iscarried out in a suitable solvent under cooling or heating, for example,at a temperature of -10° C. to 80° C., preferably at room temperature.The solvent includes, for example, methylene chloride, chloroform,di-lower alkylformamide, acetonitrile, tetrahydrofuran, and the like.

The compounds [I] obtained above may, if necessary, be converted to eachother, for example, the compound [I] wherein R² is a carboxy-loweralkylcarbonyl group, i.e. a compound of the formula: [I-e ]: ##STR11##wherein R²⁴ is a carboxy-lower alkylcarbonyl group, and the othersymbols are the same as defined above, can be prepared by subjecting acompound of the formula [I-d]: ##STR12## wherein R²³ is a loweralkoxycarbonyl-lower alkylcarbonyl group, and the other symbols are thesame as defined above, or a salt thereof to hydrolysis.

The hydrolysis of the compound [I-d] may be carried out by aconventional manner. For example, the reaction is preferably carried outin a suitable solvent under cooling or heating, for example, at atemperature of 0° C. to 100° C., preferably at a temperature of 20° C.to 50° C., in the presence of a base (e.g. alkali metal hydroxide,etc.). The solvent includes, for example, a lower alkanol, or a mixtureof a lower alkanol and water.

In the above mentioned reactions, each starting compound can be usedeither in the form of a free base or a salt thereof. The salts of thecompounds [I-a] and [I-d] are, for example, alkali metal salts, alkalineearth metal salts, heavy metal salts, organic amine salts, inorganic ororganic acid salts, and the like. The salts of the compound [II] are,for example, hydrochloride, hydrobromide, oxalate, and the like. Thesalts of the compound [IV] are, for example, hydrochloride,hydrobromide, oxalate, and the like. The salts of the compound [V] are,for example, alkali metal salts, etc., when R³ is carboxyl group. Thesalts of the compound [VII ] are, for example, hydrochloride, etc., whenR²¹ is pyridylcarbonyl group.

When the compound [I] is obtained in the form of a racemic mixture, theracemic compound [I] may easily be optically resolved in a conventionalmanner.

When the compound [I] is the compound of the formula [I] wherein Ring Ais a protected tetarzolyl-substituted phenyl group, a protecting groupfor said carboxyl group and/or for said tetrazolyl group may easily beremoved by a conventional manner.

The starting compound [II] may be prepared by the method disclosed inJapanese Patent First Publication (KOKAI) No. 167687/1986 or JapanesePatent First Publication (KOKAI) No. 101062/1990.

The starting compound [IV] may be prepared by reacting a compound [VII]:##STR13## wherein R⁶ and R⁷ are each hydrogen atom or a protecting groupfor amino group, and R¹ is the same as defined above, with the compound[III] under the same conditions as the reaction between the compound[II] and the compound [III] , followed by removing the protecting groupwhen R⁶ and/or R⁷ are a protecting group for amino group.

In the present specification, the lower alkyl group and the lower alkoxygroup mean ones having 1 to 6 carbon atoms, preferably 1 to 4 carbonatoms.

The present invention is illustrated in more detail by the followingExamples and Reference Examples, but should not be construed to belimited thereto.

EXAMPLE 1

Methyl5-diphenylacetyl-4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine-4-carboxylate(1.60 g) is dissolved in dimethylformamide (20 ml), and thereto is addedsodium hydride (60% oil-dispersion, 176 mg) under ice-cooling. Themixture is stirred at 0° C. for 20 minutes, and thereto is added[2'-(1-trityl-1H-tetrazol-5-yl)bipheyl-4-yl]methyl bromide (2.40 g), andthe mixture is stirred under ice-cooling for one hour, and further atroom temperature for one hour. The reaction solution is concentratedunder reduced pressure, and to the residue are added chloroform andwater. The organic layer is dried, and evaporated to remove the solvent.The resulting residue is purified by silica gel column chromatography(solvent; chloroform/methanol=100:1) to give methyl5-diphenylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(430 mg) as a colorless foam.

FAB-MS (m/z): 852 (M+H), 792, 610, 567, 244 NMR (CDCl₃) δ: 3.56 (3H, s),5.12 (2H, ABq)

Subsequently, there is obtained methyl5-diphenylacetyl-1-[2'-(1-trityl-1H-tetrazol-5-yl]biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.17 g) as a colorless foam.

FAB-MS (m/z): 852 (M+H), 792, 610, 567, 244 NMR (CDCl₃) δ: 3.79 (3H, s),4.81 (2H, s)

EXAMPLE 2

To a mixture of methyl5-diphenylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(400 mg) and chloroform (1 ml) is added 18% hydrochloric acid-methanol(5 ml), and the mixture is stirred at room temperature for 30 minutes.After the reaction is completed, the mixture is evaporated to remove thesolvent, and the resulting residue is dissolved in methanol (5 ml), andthe mixture is adjusted to pH 10-12 with 1N aqueous sodium hydroxidesolution, and further stirred at room temperature for 3 hours. Theresulting triphenylmethane is removed by extraction with ether, and theaqueous layer is evaporated under reduced pressure. The resultingresidue is dissolved in a small amount of water, and purified by columnchromatography of nonionic adsorbing resin (tradename; HP-20,manufactured by Mitsubishi Kasei Corporation, Japan) and lyophilized togive the following compounds.

5-Diphenylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylicacid disodium salt (170 mg)

IR (Nujol; cm⁻¹): 1630

EXAMPLE 3

A mixture of2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazolehydrochloride (8.09 g), glyoxylic acid hydrate (1.73 g), 1N aqueoussodium hydroxide solution (53 ml) and dioxane (50 ml) is stirred at 50°C. for two days. The reaction solution is acidified with hydrochloricacid, and evaporated under reduced pressure. The residue is dissolved inmethanol (100 ml), and the mixture is cooled to -30° C., and thereto isadded dropwise thionyl chloride (12.4 g). After addition, the mixture isstirred at 60° C. for two days. The mixture is evaporated under reducedpressure to remove the solvent. The mixture is neutralized with aqueoussodium hydrogen carbonate solution, and extracted with chloroform. Theextract is dried, and evaporated under reduced pressure, and theresulting oily product is purified by silica gel column chromatography(solvent; chloroform/methanol=15:1) to give methyl2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5,c]pyridine-4-carboxylate (3.74 g) as a powder.

FAB-MS (m/z): 472 (M+H) (base) NMR (DMSO-d₆) δ: 0.90 (3H, t), 3.72 (3H,s), 5.20 (2H, s)

EXAMPLE 4

To a mixture of the compound obtained in Example 3 (296 mg),triethylamine (317 mg) and chloroform (10 ml) is added dropwise asolution of acetyl chloride (148 mg) in chloroform (1 ml) underice-cooling. The mixture is stirred at room temperature for two hours,and the reaction solution is washed, dried and evaporated to remove thesolvent. The resulting residue is purified by silica gel columnchromatography (solvent; chloroform/methanol=30:1) to give methyl5-acetyl-2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(158 mg).

FAB-MS (m/z): 514 (M+H), 119 (base) NMR (CDCl₃) δ: 0.94 (3H, t), 2.16(3H, s), 3.78 (3H, s)

EXAMPLE 5

A mixture of the compound obtained in Example 3 (361 mg), methylenechloride (10 ml), triethylamine (85 mg), benzoic acid (103 mg),N-hydroxybenzotriazole (114 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (162 mg) isstirred at room temperature overnight. The reaction solution is washed,dried and evaporated to remove the solvent. The resulting oily residueis purified by silica gel column chromatography (solvent;chloroform/methanol=20:1) to give methyl2-butyl-5-benzoyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(297 mg).

FAB-MS (m/z): 576 (M+H), 105 (base) NMR (CDCl₃) δ: 0.97 (3H, t), 3.79(3H, s)

EXAMPLE 6

The compound obtained in Example 3 (483 mg) and thiophen-2-carboxylicacid (158 mg) are treated in the same manner as in Example 5 to givemethyl2-n-butyl-5-(2-thienyl)carbonyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(306 mg).

FAB-MS (m/z): 582 (M+H), 111 (base) NMR (CDCl₃) δ: 0.95 (3H, t), 3.73(3H, s)

EXAMPLE 7

A mixture of the compound obtained in Example 3 (2.98 g), 1N aqueoussodium hydroxide solution (14 ml) and methanol (30 ml) is stirred atroom temperature overnight, and evaporated to remove the solvent.

The residue is recrystallized from aqueous methanol and collected togive2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylicacid (2.11 g).

m.p. 216°-217° C. (decomposed). NMR (DMSO-d₆) δ: 0.97 (3H, t), 4.37 (1H,s), 5.17 (1H, d), 6.01 (1H, d)

EXAMPLE 8

A mixture of the compound obtained in Example 4 (142 mg), 1N aqueoussodium hydroxide solution (0.60 ml) and methanol (5 ml) is stirred atroom temperature overnight, and evaporated under reduced pressure toremove the solvent. The resulting residue is purified by columnchromatography of nonionic adsorbing resin (tradename; HP-20,manufactured by Mitsubishi Kasei Corporation, Japan), and lyophilized togive2-n-butyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylicacid disodium salt (100 mg).

m.p.>265° C. IR (Nujol; cm⁻¹): 1620

EXAMPLES 9-10

The compounds obtained in Examples 5-6 are treated in the same manner asin Example 8 to give the following compounds listed in Table 1.

                  TABLE 1                                                         ______________________________________                                         ##STR14##                                                                                        IR (Nujol;                                                Ex.  R.sup.2        cm.sup.-1) m.p. (°C.)                              ______________________________________                                         9                                                                                  ##STR15##     1620       >200 (decomposed)                              10                                                                                  ##STR16##     1620       >72 (wet)                                      ______________________________________                                    

EXAMPLE 11

(1) To a mixture of2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(3.66 g) and methanol (30 ml) is added 9% hydrochloric acid-methanol (50ml), and the mixture is stirred at room temperature for 40 minutes. Themixture is evaporated under reduced pressure to remove the solvent, andwater is added to the residue. The mixture is washed with ethyl acetate,and the aqueous layer is evaporated under reduced pressure and furthersubjected to azeotrophic distillation with toluene to give crude2-n-propyl-4-(2-aminoethyl)-1-[2'-tetrazol-5-yl)biphenyl-4-yl]methylimidazole hydrochloride (2.68 g).

(2) The above compound (2.15 g) is treated in the same manner as inExample 3 to give methyl2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.76 g) as a foam.

FAB-MS (m/z): 458 (M+H), 207 (base) NMR (DMSO-d₆) δ: 0.98 (3H, t), 3.84(3H, s), 5.06 (2H, ABq)

EXAMPLE 12

2-n-Butyl-4-(2-aminoethyl)-1-(2'-methoxycarbonylbiphenyl-4-yl)methylimidazolehydrochloride (1.80 g) is treated in the same manner as in Example 3 togive crude methyl2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.70 g).

EXAMPLE 13

To a mixture of the compound obtained in Example 12 (1.70 g) andpyridine (20 ml) is added acetic anhydride (5 ml), and the mixture isstirred overnight. The solvent is distilled off, and to the resultingresidue is added chloroform, and the mixture is washed, dried, andevaporated to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/ethanol=10:1) to give methyl2-n-butyl-5-acetyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.47 g) as an oil. NMR (CDCl₃) δ: 0.88 (3H, t),2.21 (3H, s), 3.46 (3H, s), 3.64 (3H, s), 5.33 (2H, ABq)

EXAMPLE 14

A mixture of2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazolehydrochloride (0.278 g), ethyl glyoxylate (0.179 g) and ethanol (5 ml)is refluxed for three days. To the mixture is added chloroform, and themixture is washed, dried and evaporated to remove the solvent. Theresidue is purified by silica gel column chromatography (solvent;chloroform/methanol=10:1) to give ethyl2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.136 g) as a foam.

NMR (CDCl₃) δ: 0.92 (3H, t), 1.35 (3H, t), 5.08 (2H, ABq)

EXAMPLE 15

To a mixture of2-n-butyl-4-(2-t-butoxycarbonyl-aminoethyl)-1-(2'-methoxycarbonylbiphenyl-4-yl)methylimidazole(2.02 g) and chloroform (50 ml) is added trifluorcacetic acid (25 ml),and the mixture is stirred at room temperature for 30 minutes. Themixture is evaporated under reduced pressure to remove the solvent, andto the residue are added tetrahydrofuran (30 ml), water (1 ml) andsodium hydrogen carbonate (1.13 g), and the mixture is stirred. To themixture is added chloroform, and the mixture is dried, and evaporatedunder reduced pressure to remove the solvent. To the residue are addedethyl glyoxylate hydrate (0.570 g) and ethanol (40 ml), and the mixtureis refluxed for 15 minutes. The solvent is distilled off under reducedpressure, and the resulting residue is purified by silica gel columnchromatography (solvent; chloroform/ethanol=20:1) to give ethyl2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.551 g) as a foam.

NMR (CDCl₃) δ: 0.89 (3H, t), 1.23 (3H, t), 3.65 (3H, s), 5.24 (2H, ABq)

EXAMPLES 16-31

The compounds obtained in Examples 3, 11 and 15 are treated in the samemanner as in Example 4 or 5 to give the following compounds listed inTables 2 and 3.

                  TABLE 2                                                         ______________________________________                                         ##STR17##                                                                                                     NMR    FAB-MS                                Ex.  R.sup.2         R.sup.8                                                                              R.sup.9                                                                            (CDCl.sub.3)                                                                         (m/z)                                 ______________________________________                                        16   COCH.sub.3      CH.sub.3                                                                             Tet  1.04   500                                                                    (3H, t)                                                                              (M + 1)                                                                2.17                                                                          (3H, s)                                                                       3.75   207                                                                    (3H, s)                                                                              (base)                                17   COCH.sub.2 COOCH.sub.2 CH.sub.3                                                               CH.sub.3                                                                             Tet  1.03   572                                                                    (3H, t)                                                                              (M + 1)                                                                1.18                                                                          (3H, t)                                                                       3.37   207                                                                    (3H, s)                                                                              (base)                                ______________________________________                                         Tet: 1HTetrazol-5-yl group                                               

                                      TABLE 3                                     __________________________________________________________________________     ##STR18##                                                                    Ex.                                                                              R.sup.2         R.sup.8                                                                            R.sup.9                                                                             NMR (CDCl.sub.3)                                                                      FAB-MS (m/z)                            __________________________________________________________________________    18                                                                                ##STR19##      CH.sub.3                                                                           Tet   0.96(3H, t) 3.59(2H, s) 3.69(3H,                                                      648 (M + 1) 154 (base)                  19                                                                                ##STR20##      CH.sub.3                                                                           Tet   0.97(3H, t) 3.75(3H, s) 3.78(2H,                                                      624 (M + 1) 207 (base)                  20                                                                                ##STR21##      CH.sub.3                                                                           Tet   0.95(3H, t) 3.75(3H, s) 6.46-6.48 (1H,                                                566 (M + 1) 119 (base)                  21                                                                                ##STR22##      CH.sub.3                                                                           Tet   0.96(3H, t) 3.77(3H, s) 8.58-8.62 (1H,                                                577 (M+ 1) 207 (base)                   22 --COCH.sub.2 CH.sub.3                                                                         CH.sub.3                                                                           Tet   0.96(3H, t)                                                                           528 (M + 1)                                                           1.08 (3H, t)                                                                          207 (base)                                                            3.75(3H, s)                                     23 --COCH.sub.2 CH.sub.2 COOCH.sub.3                                                             CH.sub.3                                                                           Tet   0.96(3H, t)                                                                           586 (M + 1)                                                           3.46(3H, s)                                                                           207 (base)                                                            3.72(3H, s)                                     24                                                                                ##STR23##      CH.sub.3                                                                           Tet   0.85-1.01 (3H, m) 3.80(3H, s) 8.66-8.71                                       (1H, m) 577 (M + 1) 207 (base)                  25 --COCH(CH.sub.3).sub.2                                                                        CH.sub.3                                                                           Tet   0.96(3H, t)                                                                           542 (M + 1)                                                           1.08(3H, d)                                                                           207 (base)                                                            1.11(3H, d)                                     26 --SO.sub.2 CH.sub.3                                                                           CH.sub.3                                                                           Tet   0.96(3H, t)                                                                           550 (M + 1)                                                           3.00(3H, s)                                                                           154 (base)                                                            3.77(3H, s)                                     27 --COOCH.sub.2 CH.sub.3                                                                        CH.sub. 3                                                                          Tet   0.94(3H, t)                                                                           544 (M + 1)                                                           1.23(3H, t)                                                                           207 (base)                                                            3.69(3H, s)                                     28 --COCH.sub.2 SCH.sub.3                                                                        CH.sub.3                                                                           Tet   0.96(3H, t)                                                                           560 (M + 1)                                                           2.11(3H, s)                                                                           154 (base)                                                            3.75(3H, s)                                     29 --COCH.sub.2 COOCH.sub.2 CH.sub.3                                                             CH.sub.2 CH.sub.3                                                                  COOCH.sub.3                                                                         0.84-0.96                                                                             590 (M + 1)                                                           (3H, m) 225 (base)                                                            3.57(2H, s)                                     30 --COCH.sub.2 COOCH.sub.2 CH.sub.3                                                             CH.sub.3                                                                           Tet   0.95(3H, t)                                                                           586 (M + 1)                                                           1.18(3H, t)                                                                           207 (base)                                                            3.50(2H, s)                                                                   5.28(2H, ABq)                                                                 5.40(1H, s)                                     31 --COCH.sub.2 CN CH.sub.3                                                                           Tet   0.94(3H, t)                                                                           539 (M + 1)                                                           3.67(3H, s)                                                                   3.75(3H, s)                                                                   5.29(2H, s)                                     __________________________________________________________________________     Tet: 1HTetrazol-5-yl group                                               

EXAMPLE 32

To a mixture of the compound obtained in Example 3 (0.50 g) and methanol(10 ml) is added diketene (0.20 g), and the mixture is stirred at roomtemperature for two hours. The mixture is evaporated under reducedpressure to remove the solvent, and to the residue is added chloroform.The mixture is washed, dried and evaporated under reduced pressure. Theresulting residue is purified by silica gel column chromatography(solvent; chloroform/ethyl acetate/methanol=10:10:1) to give methyl2-n-butyl-5-acetoacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.29 g) as a foam.

FAB-MS (m/z): 556 (M+1), 207 (base) NMR (CDCl₃) δ: 0.96 (3H, t), 2.22(3H, s), 3.74 (3H, s)

EXAMPLE 33

To a mixture of the compound obtained in Example 16 (0.131 g) andmethanol (2 ml) is added 0.5M aqueous sodium hydrogen carbonate solution(0.53 ml). Five minutes thereafter, the mixture is evaporated underreduced pressure to remove the solvent, and the residue is purified bycolumn chromatography of nonionic adsorbing resin (tradename; HP-20,manufactured by Mitsubishi Kasei Corporation, Japan), and lyophilized togive methyl2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7tetrahydroimidazo[4,5-c]pyridine-4-carboxylate sodium salt (0.089 g) as a powder.

m.p.>196° C. (decomposed) NMR (DMSO-d₆) δ: 0.83-0.92 (3H, m), 1.92 and2.12 (3H, s), 3.27 and 3.32 (3H, s)

EXAMPLES 34-37

The compounds obtained in Examples 4, 20, 21 and 24 are treated in thesame manner as in Example 33 to give the following compounds listed inTable 4.

                  TABLE 4                                                         ______________________________________                                         ##STR24##                                                                    Ex.      R.sup.2         NMR (D.sub.2 O)                                      ______________________________________                                        34                                                                                      ##STR25##      0.73(3H, t) 3.10-3.90(4H, b)                         35                                                                                      ##STR26##      0.82(3H, t) 3.25 and 3.56(3H, s)                     36                                                                                      ##STR27##      0.69-0.81(3H, m) 3.23 and 3.62(3H, s)                37       COCH.sub.3      0.71-0.80(3H, m)                                                              3.21 and 3.47(3H, s)                                 ______________________________________                                    

EXAMPLES 38-46

The compounds obtained in Examples 13, 16, 20-25 and 27 are treated inthe same manner as in Example 8 to give the following compounds listedin Table 5.

                  TABLE 5                                                         ______________________________________                                         ##STR28##                                                                                                         IR (Nujol;                               Ex.  R.sup.1    R.sup.2        R.sup.9                                                                             cm.sup.-1)                               ______________________________________                                        38   --(CH.sub.2).sub.2 CH.sub.3                                                              --COCH.sub.3   Tet   1610                                     39   --(CH.sub.2).sub.3 CH.sub.3                                                               ##STR29##     Tet   1620                                     40   --(CH.sub.2).sub.3 CH.sub.3                                                               ##STR30##     Tet   1620                                     41   --(CH.sub.2).sub.3 CH.sub.3                                                              --COCH.sub.2 CH.sub.3                                                                        Tet   1620                                      42* --(CH.sub.2).sub.3 CH.sub.3                                                              --COCH.sub.2 CH.sub.2 COOH                                                                   Tet   1620-1560                                43   --(CH.sub.2).sub.3 CH.sub.3                                                               ##STR31##     Tet   1620                                     44   --(CH.sub.2).sub.3 CH.sub.3                                                              --COCH(CH.sub.3).sub.2                                                                       Tet   1620                                     45   --(CH.sub.2).sub.3 CH.sub.3                                                              --COOCH.sub.2 CH.sub.3                                                                       Tet   1680, 1610                               46   --(CH.sub.2).sub.3 CH.sub.3                                                              --COCH.sub.3   COOH  1630-1560                                ______________________________________                                         *The compound of Example 42 is trisodium salt.                                Tet: 1HTetrazol-5-yl group                                               

EXAMPLE 47

(1) To a mixture of methyl2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(2.0 g), triethylamine (0.69 g) and chloroform (20 ml) is added tritylchloride (1.43 g), and the mixture is stirred at room temperature for 30minutes. The reaction solution is washed, dried, and evaporated underreduced pressure. The resulting residue is purified by silica gel columnchromatography (solvent; ethyl acetate/n-hexane) to give methyl2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxytate(1.29 g) as needles.

m.p. 124°-126° C. (decomposed)

(2) The above product is optically resolved by HPLC columnchromatography for separation of optically active isomers (tradename;Chiralcel OD, manufactured by Daicel Chemical Industries, Ltd., Japan)(solvent; n-hexane/ethanol=7:3) to give the (+)-isomer and the(-)-isomer separately.

The (+)-isomer:

[α]_(D) :+25.2° (c=0.5, chloroform, 25° C.)

The (-)-isomer:

[α]_(D) :-22.8° (c=0.5, chloroform, 25° C.)

EXAMPLE 48

To a mixture of methyl(+)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(395 mg) and tetrahydrofuran (4 ml) is added 90% formic acid (8 ml)under ice-cooling, and the mixture is stirred at-room temperature for 30minutes, and evaporated under reduced pressure to remove the solvent.The resulting residue is purified by silica gel column chromatography(solvent; chloroform/methanol) to give methyl(+)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(270 mg) as a foam.

[α]_(D) : +70.4° (c=0.5, chloroform, 20° C.)

EXAMPLE 49

Methyl(-)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylateis treated in the same manner as in Example 48 to give methyl(-)-2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylateas a foam.

[α]_(D) :-70.8° (c=0.5, chloroform, 20° C.)

EXAMPLE 50

2-n-Propyl-5-(2-aminoethyl)-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(1.01g) is dissolved in tetrahydrofuran (10 ml), and thereto is addedethyl glyoxylate hydrate (195 mg), and the mixture is stirred at roomtemperature overnight. The mixture is heated at 50° C. for 30 minutes,and after cooling, 7% hydrochloric acid-methanol solution (3 ml) andchloroform (10 ml) are added to the mixture, which is refluxed for 20minutes. The mixture is evaporated under reduced pressure to remove thesolvent, and the resulting residue is dissolved in chloroform (30 ml).To the mixture are added acetic anhydride (290 mg) and a solution ofsodium hydrogen carbonate (1.2 g) in water (20 ml), and the mixture isstirred at room temperature overnight. The mixture is acidified withcitric acid, and extracted with chloroform. The extract is washed withwater, dried, and evaporated. To the residue are added fumaric acid (100mg) and ethanol (35 ml), and the mixture is refluxed for 5 hours. Then,the reaction mixture is evaporated under reduced pressure, and theresidue is recrystallized from methanol/ether to give ethyl2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate1/2 fumarate (728 mg).

m.p. 184°-185° C. Yield: 80%

EXAMPLE 51

To a mixture of2-n-propyl-4-(2-aminoethyl)-1-[2'-1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(21.95 g) and tetrahydrofuran (200 ml) is added a solution of ethylglyoxylate hydrate (4.25 g) in tetrahydrofuran (20 ml) at 5° C. Themixture is stirred overnight at room temperature and refluxed for 30minutes. To a mixture is added a 8% hydrogen chloride ethanol solution(100 ml) at room temperature. The reaction mixture is stirred for 30minutes, then evaporated. The residue is dissolved in chloroform andwashed successively with a saturated sodium hydrogen carbonate solutionand brine. The organic layer is dried and evaporated. The oxalate isrecrystallized from ethanol to give ethyl2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylateoxalate (10.84 g).

m.p. 140°-142° C. NMR (DMSO-d₆) δ: 0.84 (3H, t), 4.95 (1H, s), 5.29 (2H,brs)

Free carboxylic acid

NMR (CDCl₃) δ: 1.00 (3H, t), 3.98 (1H, s), 5.09 (2H, q)

EXAMPLES 52-59

The compound obtained in Example 11 and the corresponding startingcompounds are treated in the same manner as in Example 4 or 5 to givethe following compounds listed in Tables 6 and 7.

                  TABLE 6                                                         ______________________________________                                         ##STR32##                                                                    Ex.                 NMR         FAB-MS (m/z)                                  ______________________________________                                        52                                                                                     ##STR33##  1.01(3H, t) 3.71(3H, s)                                                                   552 (M.sup.+  + H) 95 (base)                  53      CH(CH.sub.3).sub.2                                                                        1.00-1.13(9H)                                                                             528 (M.sup.+  + H)                                                3.70(3H, s) 149 (base)                                    ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR34##                                                                    Ex.  R              NMR         FAB-MS (m/z)                                  ______________________________________                                        54   --CH.sub.2 CH.sub.3                                                                          1.03(3H, t) 528 (M.sup.+  + H)                                                5.29(2H, s) 207 (base)                                                        5.42(1H, s)                                               55   --(CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                        1.04(3H, t) 600 (M.sup.+  + H)                                                5.28(2H, ABq)                                                                             207 (base)                                                        5.32(1H, s)                                               56   --OCH.sub.2 CH.sub.3                                                                         1.00(3H, t) 544 (M.sup.+  + H)                                                4.95(1H, s) (base)                                                            5.29(2H, s) 207                                           57   --N(CH.sub.3).sub.2                                                                          1.01(3H, t) 543 (M.sup.+  + H)                                                5.28(2H, ABq)                                                                             72 (base)                                                         4.77(1H, s)                                               58   --CH.sub.2 CN  0.99(3H, t) 539 (M.sup.+  + H)                                                1.26(3H, t) 207 (base)                                                        1.84(2H, dt)                                                                  5.95(1H, s)                                               59   --CH.sub.2 NHCOCH.sub.3                                                                      1.00, 1.03  571 (M.sup.+  + H)                                                (3H, each t)                                                                              207 (base)                                                        1.32(3H, t)                                                                   1.94, 1.97                                                                    (3H, each s)                                              ______________________________________                                    

EXAMPLE 60

Ethyl2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.00 g) is treated in the same manner as in Example 32 with usingethanol instead of methanol to give ethyl2-n-propyl-5-acetoacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.00 g) as a white foam.

NMR (CDCl₃) δ: 1.03 (3H, t), 2.22 (3H, s), 3.61 (2H, ABq), 5.30 (2H,ABq), 5.36 (1H, s)

EXAMPLE 61

To a mixture of ethyl2-n-propyl-5-acetoacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(200 mg), magnesium chloride (34 mg), pyridine (58 μl) and acetonitrile(2 ml) is added benzoyl chloride (42 μl) under ice-cooling. The reactionmixture is stirred overnight at room temperature, then diluted withchloroform (50 ml). The solution is washed with 10% hydrochloric acidand brine, dried, and evaporated to give a crude product (266 mg) as anoil. The product (260 mg) obtained above is refluxed with 10%hydrochloric acid (1.0 ml) in ethanol (5.0 ml) for one hour. Thereaction mixture is diluted with chloroform (30 ml), washed with brine,dried, and then evaporated. Purification by silica gel columnchromatography (solvent; chloroform/ethanol) gives ethyl 2-n-propyl-5-benzoylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(144 mg) as a white foam.

FAB-MS (m/z): 618 (MH⁺), 207 (base) NMR (CDCl₃) δ: 1.04 (3H, t),4.00-4.28 (5H, m), 5.30 (2H, s), 5.40 (1H, s)

EXAMPLE 62

To a mixture of2-n-propyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole(10.0 g) and tetrahydrofuran (100 ml) is added a solution of ethylglyoxylate hydrate (2.90 g) in tetrahydrofuran at room temperature. Thereaction mixture is stirred overnight, refluxed for 30 minutes, andevaporated. The residue is dissolved in chloroform and the solution iswashed with 2% hydrochloric acid solution, a saturated sodium hydrogencarbonate solution and brine. The organic layer is dried and evaporated.The crude product is crystallized with oxalic acid from ethanol-ether togive ethyl2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylateoxalate (8.45 g).

m.p. 166°-168° C. NMR (DMSO-d₆) δ: 0.87 (3H, t), 1.25 (9H, s), 5.10 (1H,s), 5.40 (2H, s)

EXAMPLE 63

The compound obtained in Example 62 (1.00 g) is suspended in chloroform.The suspension is washed with a saturated sodium hydrogen carbonatesolution and brine, dried over magnesium sulfate and evaporated. To amixture of the crude substrate (0.75 g), ethoxycarbonylacetic acid (0.33g) and methylene chloride (10 ml) is added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48 g) atroom temperature. The reaction mixture is stirred for one hour, andwashed with 10% citric acid solution, a saturated sodium hydrogencarbonate solution and brine. The organic layer is dried and evaporated.The crude product is purified by silica gel column chromatography(solvent; chloroform/ethyl acetate) to give ethyl2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4-carboxylate(0.70 g).

FAB-MS (m/z): 618 (MH⁺), 211 (base) NMR (CDCl₃) δ: 1.12 (3H, t), 1.28(9H, s), 3.57 (2H, s), 5.37 (2H, ABq)

EXAMPLE 64

To a mixture of the compound obtained in Example 62 (1.00 g), sodiumhydrogen carbonate (1.41 g), chloroform (20 ml) and water (10 ml) isadded acetic anhydride (516 mg) at room temperature. The mixture isstirred overnight. The organic layer is separated, washed with brine,dried, and evaporated. Silica gel column chromatography (solvent;chloroform/methanol=20:1) gives ethyl2-n-propyl-5-acetyl-3-[2-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.90 g) as awhite foam.

FAB-MS (m/z): 546 (MH⁺), 211 (base) NMR (CDCl₃) δ: 0.94 (3H, t), 1.28(9H, s), 5.37 (2H, ABq), 6.02 (1H, s)

EXAMPLE 65

The compound obtained in Example 62 (1.0 g) is treated in the samemanner as in Example 64 with using propionyl chloride (0.23 g) insteadof acetic anhydride to give ethyl2-n-propyl-5-propionyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.82 g) as a white foam.

FAB-MS (m/z): 560 (MH⁺), 211 (base) NMR (CDCl₃) δ: 0.94 (3H, t), 1.12(3H, t), 1.18 (3H, t), 1.29 (9H, s)

EXAMPLE 66

The compound obtained in Example 62 (1.00 g) is treated in the samemanner as in Example 64 with using ethyl chloroformate (0.27 g) insteadof acetic anhydride to give ethyl2-n-propyl-5-ethoxycarbonyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.82 g) as a white foam.

FAB-MS (m/z): 576 (MH⁺), 211 (base) NMR (CDCl₃) δ: 0.95, 0.96 (3H, t),1.12-1.31 (15H, m), 5.22-5.60 (3H, m)

EXAMPLE 67

The mixture of ethyl2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) isstirred overnight at room temperature. The reaction mixture is washedwith a saturated sodium hydrogen carbonate solution and brine, dried,and evaporated. The crude product is purified by silica gel columnchromatography (solvent; chloroform/methanol) to give ethyl2-n-propyl-3-(2'-carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(516 mg).

FAB-MS (m/z): 562 (MH⁺), 211 (base) NMR (CDCl₃) δ: 0.76 (3H, t), 3.55(2H, s), 5.34 (2H, ABq)

EXAMPLES 68-70

The compounds obtained in Examples 64 to 66 are treated in the samemanner as in Example 67 to give the following compounds listed in Table8.

                  TABLE 8                                                         ______________________________________                                         ##STR35##                                                                    Ex.    R         NMR (CDCl.sub.3) δ                                                                    DI-EI-MS (m/z)                                 ______________________________________                                        68     --CH.sub.3                                                                              0.79(3H, t)   489 (M.sup.+)                                                   2.18(3H, s)   416 (base)                                                      5.93(1H, s)                                                  69     --C.sub.2 H.sub.5                                                                       0.81(3H, t)   503(M.sup.+)                                                    1.15(3H, t)   430 (base)                                                      1.18(3H, t)                                                                   5.91(1H, s)                                                  70     --OC.sub.2 H.sub.5                                                                      0.68, 0.75(3H, t)                                                                           519 (M.sup.+)                                                   1.13-1.51(8H, m)                                                                            446 (base)                                                      5.15-5.54(3H, m)                                             ______________________________________                                    

EXAMPLE 71

2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethylglyoxylate hydrate (1.56 g). The reaction mixture is stirred overnightat room temperature and then refluxed for one hour. The solution isevaporated and the residue is purified by silica gel columnchromatography (solvent; chloroform/methanol) to give ethyl2-ethyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(5.54 g) as a foam, characterized as its oxalate.

m.p. 142°-146° C. NMR (DMSO-d₆) δ: 4.93 (1H, s), 5.23 (2H, s)

EXAMPLE 72

A solution of ethyl2-ethyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.94 g), monoethyl malonate (0.74 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.80 g),triethylamine (1.40 g) in dichloromethane (20 ml) is stirred overnightat room temperature. The reaction mixture is washed with water and driedover sodium sulfate, and then evaporated. The residue is dissolved inethanol (30 ml), fumaric acid (2.00 g) is added, and the solution isrefluxed for three hours. The solvent is evaporated and the residue istreated with a saturated sodium hydrogen carbonate solution and thenextracted with chloroform. The organic layer is dried and evaporated.Purification by silica gel column chromatography (solvent;chloroform/methanol) gives ethyl2-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.07 g) as a foam.

NMR (CDCl₃) δ: 5.29 (2H, s), 5.48 (1H, s), 6.92 (2H, d), 7.10 (2H, d)

EXAMPLE 73

A mixture of ethyl2-ethyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.51 g), acetic anhydride (0.44 g), sodium hydrogen carbonate (1.09 g),chloroform (18 ml)and water (18 ml) is stirred overnight at roomtemperature. The aqueous layer is extracted with chloroform, and thecombined organic layer is washed with aqueous citric acid solution andbrine, dried, and evaporated. To the residue (1.46 g) is added fumaricacid (1.2 g) and ethanol (20 ml), and the mixture is refluxed for fourhours, then evaporated. The residue is treated with a saturated sodiumhydrogen carbonate solution and then extracted with chloroform. Theorganic layer is dried and evaporated. Purification by silica gel columnchromatography (solvent; chloroform/methanol) gives ethyl2-ethyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.76 g) as a white foam.

FAB-MS (m/z): 500 (M+1, base), 207 NMR (CDCl ₃) δ: 1.30 (3H, t), 2.16(3H, s), 5.30 (2H, s), 5.45 (1H, s)

EXAMPLE 74

To a solution of2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole(5.30 g) in tetrahydrofuran (40 ml) is added ethyl glyoxylate hydrate(1.67 g). The reaction mixture is stirred overnight at room temperatureand then refluxed for two hours. The solvent is evaporated and theresidue is purified by silica gel column chromatography (solvent;chloroform/methanol) to give ethyl2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(5.90 g) as a yellow oil.

FAB-MS (m/z): 490 (M+1), 211 (base) NMR (CDCl₃) δ: 1.22 (3H, t), 1.28(9H, s), 1.31 (3H, t), 4.36 (1H, s)

EXAMPLE 75

A mixture of ethyl2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(2.26 g), acetic anhydride (0.94 g), sodium hydrogen carbonate (2.33 g),chloroform (18 ml) and water (18 ml) is stirred overnight at roomtemperature. The organic layer is separated, washed with brine, dried,and evaporated. The residue is purified by silica gel columnchromatography (solvent; chloroform/methanol) to give ethyl2-ethyl-5-acetyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(2.10 g) as a white foam.

FAB-MS (m/z): 532 (M+1), 211 (base) NMR (CDCl₃) δ: 1.13 (3H, t), 1.28(9H, s), 2.22 (3H, s), 6.05 (1H, s)

EXAMPLE 76

A solution of ethyl2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.72 g), monoethyl malonate (0.94 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 g),triethylamine (1.78 g) in dichloromethane (20 ml) is stirred overnightat room temperature. The reaction mixture is washed with water and driedover sodium sulfate and then evaporated. The residue is purified bysilica gel column chromatography (solvent; chloroform/methanol) to giveethyl2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.57 g) as an oil. NMR (CDCl₃) δ: 1.12 (3H, t), 1.28 (9H, s), 5.35 (2H,q), 6.00 (1H, s)

EXAMPLE 77

To a solution of the above product (2.05 g) in dichloromethane (20 ml)is added trifluoroacetic acid (6 ml). The reaction mixture is stirred atroom temperature overnight, and then evaporated. The residue isdissolved in chloroform and washed with a saturated sodium hydrogencarbonate solution. The organic layer is dried over sodium sulfate andthen concentrated to give the crude product which is purified by silicagel column chromatography (solvent; chloroform/methanol) to give ethyl2-ethyl-3-(2'-carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.17 g) as a white foam.

NMR (CDCl₃) δ: 0.98 (3H, t), 1.16 (3H, t), 1.27 (3H, t), 5.33 (2H, q),6.00 (1H, s)

EXAMPLE 78

The compound obtained in Example 75 (2.05 g) is treated in the samemanner as in Example 67 to give ethyl2-ethyl-5-acetyl-3-(2'-carboxybiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.53 g) as a white foam.

FAB-MS (m/z): 476 (M+1), 211 (base) NMR (CDCl₃) δ: 1.00 (3H, t), 2.20(3H, s), 6.00 (1H, s), 6.95 (2H, d)

EXAMPLE 79

A mixture of ethyl2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.20 g), potassium carbonate (0.082 g), allyl bromide (0.057 g) andtetrahydrofuran (2 ml) is stirred overnight at room temperature. To themixture is added chloroform, and the mixture is washed, dried andevaporated. The residue is purified by silica gel column chromatography(solvent; chloroform/methanol) to give ethyl2-n-propyl-5-allyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.128 g).

FAB-MS (m/z): 544 (M+1), 211 (base) NMR (CDCl₃) δ: 0.96 (3H, t), 1.19(3H, t), 1.30 (9H, s), 4.25 (1H, s)

EXAMPLE 80

To a mixture of ethyl2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.65 g), potassium carbonate (0.533 g) and dimethylformamide (6 ml) isadded benzyl bromide (0.33 g). The mixture is stirred at roomtemperature for one hour, then diluted with ethyl acetate. The solutionis washed with water, dried, and evaporated. The residue is purified bysilica gel column chromatography (solvent; chloroform/methanol) to giveethyl2-n-propyl-5-benzyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.49 g).

FAB-MS (m/z): 594 (M+1), 91 (base) NMR (CDCl₃) δ: 0.96 (3H, t), 1.16(3H, t), 1.28 (9H, s), 4.22 (1H, s)

EXAMPLE 81

The compound obtained in Example 79 is treated in the same manner as inExample 67 to give ethyl2-n-propyl-5-allyl-3-(2'-carboxybiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate.

FAB-MS (m/z): 488 (M+1), 43 (base) NMR (CDCl₃) δ: 0.74 (3H, t), 1.18(3H, t), 4.34 (1H, S)

EXAMPLE 82

The compound obtained in Example 80 is treated in the same manner as inExample 67 to give ethyl2-n-propyl-5-benzyl-3-(2'-carboxybiphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate.

FAB-MS (m/z): 538 (M+1), 91 (base) NMR (CDCl₃) δ: 0.77 (3H, t), 1.09(3H, t), 3.63 (1H, d), 3.76 (1H, d), 4.18 (1H, s)

EXAMPLE 83

A mixture of2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(6.92 g), ethyl glyoxylate hydrate (1.30 g) and tetrahydrofuran (70 ml)is stirred overnight at room temperature. The mixture is evaporated, andthe residue is purified by silica gel column chromatography (solvent;chloroform/ethanol) to give ethyl2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(5.32 g) as a foam.

FAB-MS (m/z): 714 (M+1), 243 (base) NMR (CDCl₃) δ: 0.90 (3H, t), 1.21(3H, t), 1.92 (brs), 4.17 (1H, s), 5.10 (2H, ABq)

EXAMPLE 84

A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(2.00 g), potassium carbonate (1.16 g), ethyl bromide (0.61 g) anddimethylformamide (10 ml) is stirred overnight at room temperature. Themixture is diluted with ethyl acetate, and the solution is washed withwater, dried and evaporated. The residue is purified by silica gelcolumn chromatography (solvent; chloroform/methanol) to give ethyl5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.12 g) as a white foam.

FAB-MS (m/z): 742 (M+1), 243 (base) NMR (CDCl₃) δ: 0.88 (3H, t), 0.97(3H, t), 1.15 (3H, t), 4.15 (1H, s)

EXAMPLE 85

A mixture of ethyl2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(2.00 g), potassium carbonate (1.16 g), benzyl bromide (0.72 g) anddimethylformamide (10 ml) is stirred under ice-cooling for two hours.The mixture is diluted with ethyl acetate, and the solution is washedwith water, dried and evaporated. The residue is purified by silica gelcolumn chromatography (solvent; n-hexane/ethyl acetate) to give ethyl5-benzyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.50 g) as a white foam.

FAB-MS (m/z): 804 (M+1), 243 (base) NMR (CDCl₃) δ: 0.87 (3H, t), 1.13(3H, t), 3.64 (1H, d), 3.77 (1H, d), 4.13 (1H, s)

EXAMPLE 86

A mixture of ethyl5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(1.10 g), fumaric acid (1.2 g) ane ethanol (20 ml) is refluxed for onehour. The mixture is evaporated, and the residue is dissolved inchloroform, and the mixture is washed with a saturated sodium hydrogencarbonate solution and brine, dried and evaporated. The residue ispurified by silica gel column chromatography (solvent;chloroform/methanol) to give ethyl5-ethyl-2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(0.65 g) as a white foam.

FAB-MS (m/z): 500 (M+1), 43 (base) NMR (CDCl₃) δ: 0.88 (3H, t), 0.99(3H, t), 1.05 (3H, t), 4.05 (1H, s)

EXAMPLE 87

The compound obtained in Example 85 is treated in the same manner as inExample 86 to give ethyl5-benzyl-2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate.

FAB-MS (m/z): 562 (M+1), 91 (base) NMR (CDCl₃) δ: 0.89 (3H, t), 1.03(3H, t), 3.54 (1H, d), 3.68 (1H, d), 4.02 (1H, s)

EXAMPLES 88-102

The compounds obtained in Examples 52 to 56, 59, 68 to 70, 73, 78, 81,82, 86 and 87 are treated in the same manner as in Example 8 to give thefollowing compounds listed in Tables 9 to 12.

                  TABLE 9                                                         ______________________________________                                         ##STR36##                                                                    Ex.  R            NMR (D.sub.2 O) δ                                                                      FAB-MS (m/z)                                 ______________________________________                                        88                                                                                  ##STR37##   0.87(3H, t) 6.23(2H, dd)                                                                     582 (M + 1) 155 (base)                       89   --CH(CH.sub.3).sub.2                                                                       0.89(3H, t)    558 (M + 1)                                                    0.44, 0.96, 1.04, 1.14                                                                       154 (base)                                                     (6H, d)                                                     90   --CH.sub.2 CH.sub.3                                                                        0.70-1.19(6H, m)                                                                             566 (M + Na)                                                   5.14-5.78(3H, m)                                                                             544 (M + 1)                                                                   154 (base)                                   91   --(CH.sub.2).sub.2 COONa                                                                   0.76-0.92(6H, m)                                                                             632 (M + Na)                                                   5.18-5.78(3H, m)                                                                             610 (M + 1)                                                                   154 (base)                                   92   --OCH.sub. 2 CH.sub.3                                                                      0.82(3H, t)    582 (M + Na)                                                   0.94, 1.26(3H, t)                                                                            560 (M + 1)                                                                   154 (base)                                   93   --CH.sub.2 NHCOCH.sub.3                                                                    0.81, 0.93(3H, each t)                                                                       609 (M + Na)                                                   4.06, 4.56(1H, each dd)                                                                      587 (M + 1)                                                    4.45, 5.68(1H, each s)                                                                       154 (base)                                   ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                         ##STR38##                                                                    Ex.  R          m.p.     NMR (D.sub.2 O) δ                                                                 FAB-MS (m/z)                               ______________________________________                                        94   --CH.sub.3 >300° C.                                                                        0.88, 0.95                                                                              528 (M + Na)                                                        (3H, each t)                                                                            506 (M + 1)                                                         1.72, 2.21                                                                              177 (base)                                                          (3H, each s)                                         95   --CH.sub.2 CH.sub.3                                                                      >300° C.                                                                        0.72, 0.87                                                                              542 (M + Na)                                                        (3H, each t)                                                                            520 (M + 1)                                                         0.97, 1.10                                                                    (3H, each t)                                         96   --OCH.sub.2 CH.sub.3                                                                     >280° C.                                                                        0.86(3H, t)                                                                             582 (M + Na)                                                        1.27(3H, t)                                                                             560 (M + 1)                                                                   177 (base)                                 ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                         ##STR39##                                                                    Ex.   R.sup.9    NMR (D.sub.2 O) δ                                                                      FAB-MS (m/z)                                  ______________________________________                                        97    Tet        1.06-1.16(3H, m)                                                                             538 (M + Na)                                                   1.71, 2.04(3H, each s)                                                                       516 (M + 1)                                                    5.50, 6.01(1H, each s)                                                                       177 (base)                                    98    COOH       1.15(3H, t)    514 (M + Na)                                                   1.75, 2.03(3H, each s)                                                                       492 (M + 1)                                                    5.97, 6.31(1H, each s)                                                                       177 (base)                                    ______________________________________                                         Tet: 1HTetrazol-5-yl group                                               

                  TABLE 12                                                        ______________________________________                                         ##STR40##                                                                                                 NMR     FAB-MS                                   Ex.   R.sup.2       R.sup.9  (D.sub.2 O)                                                                           (m/z)                                    ______________________________________                                         99   --CH.sub.2 CH.sub.3                                                                         Tet      0.82(3H, t)                                                                           538                                                                   0.99(3H, t)                                                                           (M + Na)                                                              4.01(1H, s)                                                                           516                                                                           (M + 1)                                                                       177                                                                           (base)                                   100                                                                                  ##STR41##    Tet      0.88(3H, t) 3.84(1H, s) 4.94(1H,                                                      600 (M + Na) 578 (M + 1) 177 (base)      101   --CH.sub.2 CH═CH.sub.2                                                                  --COOH   0.90(3H, t)                                                                           526                                                                   3.99(1H, s)                                                                           (M + Na)                                                              7.05(2H, d)                                                                           504                                                                           (M + 1)                                                                       177                                                                           (base)                                   102                                                                                  ##STR42##    --COOH   0.93(3H, t) 3.52(1H, d) 3.78(1H,                                                      554 (M + 1) 177 (base)                   ______________________________________                                         Tet: 1HTetrazol-5-yl group                                               

EXAMPLE 103

To a solution of ethyl2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate(50.0 g) in methanol (500 ml) is added 4N aqueous sodium hydroxidesolution (50 ml) under ice-cooling. The mixture is stirred overnight atroom temperature, then evaporated. The residue is recrystallized fromethanol to give2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylicacid disodium salt (44.3 g).

m.p.>300° C. FAB-MS (m/z): 552 (M+Na), 530 (M+1), 177 (base) NMR (D₂ O)δ: 0.81-0.93 (3H, m), 1.67, 2.02 (3H, each s), 4.53, 5.44 (1H, each s)

Reference Example 1

Methyl 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate is treatedin the same manner as Example 5 to give methyl5-diphenylacetyl-4,5,6,7-tetrahydroimidazo[4,5c]pyridine-4-carboxylateas a pale yellow foam.

NMR (CDCl₃) δ: 3.68 (3H, s), 6.07 (1H, s)

Reference Example 2

(1) 1-t-Butoxycarbonyl-4-[2-(t-butoxycarbonylamino)ethyl]imidazole (78.1g) is dissolved in acetonitrile (500 ml), and thereto is addedmethoxymethyl chloride (22.2 g). The mixture is stirred at roomtemperature overnight, and poured into aqueous 10% sodium carbonatesolution, and extracted with ethyl acetate. The extract is washed, driedand evaporated to give5-[2-(t-butoxycarbonylamino)ethyl]1-methoxymethylimidazole (54.4 g) asan oil.

NMR (CDCl₃) δ: 1.43 (9H, s), 3.27 (3H, s), 5.20 (2H, s)

(2) The above compound (55 g) is dissolved in tetrahydrofuran (1.5liter), and the mixture is cooled to -40° C. To the mixture is addeddropwise 1.6M n-butyl lithium/n-hexane solution (150 ml), and themixture is stirred for 30 minutes. To the mixture is addedhexamethylphosphamide (150 ml), and thereto is further added n-butyllithium (137 ml), and n-butyl iodide (37.5 g) is added dropwise to themixture while the temperature thereof is kept at -30° C. The mixture isstirred for 10 minutes, and the reaction is quenched with aqueousammonium chloride solution. Ethyl acetate is-added to the reactionmixture, and the organic layer is collected, washed, dried andevaporated to remove the solvent. The resulting oily residue is purifiedby silica gel column chromatography (solvent; chloroform/ethylacetate/methanol=32:8:1) to give5-[2-(t-butoxycarbonylamino)ethyl]2-n-butyl-1-methoxymethylimidazole(44.8 g) as an oil.

NMR (CDCl₃) δ: 0.94 (3H, t), 1.44 (9H, s), 3.27 (3H, s), 5.09 (2H, s)

(3) A mixture of the above compound (80.7 g), ethyl chorocarbonate (84.5g) and chloroform (1.3 liter) is refluxed for 2.5 hours, and evaporatedto remove the solvent. Ethanol (300 ml) and 10% aqueous sodium hydroxidesolution (200 ml) are added to the residue, and the mixture is stirredunder ice-cooling for 20 minutes. The solvent is distilled off, andchloroform and water are added to the residue. The chloroform layer isdried and evaporated. The resulting residue is recrystallized fromisopropyl ether to give4-[2-(t-butoxycarbonylamino)ethyl]2-n-butylimidazole (50.3 g).

m.p. 118-120° C.

(4) The above compound is treated in the same manner as in Example 1 togive4-[2-(t-butoxycarbonylamino)ethyl]2-n-butyl-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole.

NMR (CDCl₃) δ: 0.89 (3H, t), 1.43 (9H, s), 4.85 (2H, s)

(5) A mixture of the above compound (15.2 g), 10% hydrochloric acid (40ml) and methanol (60 ml) is refluxed for one hour. After the reaction iscompleted, the mixture is evaporated to remove the methanol, and theaqueous layer is washed and concentrated to dryness under reducedpressure. The resulting residue is subjected to azeotropic distillationwith dry toluene to give crude2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazolehydrochloride (9.7 g) as a caramel.

FAB-MS (m/z): 402 (M+H) (base) NMR (DMSO-d₆) δ: 0.84 (3H, t), 1.43 (9H,s), 5.40 (2H, s)

Reference Example 3

(1) 2-Propyl-4-hydroxymethylimidazole (2.61 g) is added to thionylchloride (4.5 ml), and the mixture is heated at 50° C. for two hours.The solvent is distilled off, and the residue is dissolved indimethylformamide (20 ml), and the mixture is added dropwise to asolution of sodium cyanide (5.47 g) in dimethylformamide (120 ml). Themixture is stirred at room temperature overnight, and evaporated toremove the solvent. To the resulting residue is added ethyl acetate, andthe mixture is washed, dried and evaporated. The residue is purified bysilica gel column chromatography (solvent; ethyl acetate) to give2-n-propyl-4-cyanomethylimidazole (3.08 g) as an oil.

NMR (CDCl₃) δ: 0.95 (3H, t), 3.67 (2H, d)

(2) The above product (3.08 g) is dissolved in acetic acid (30 ml), andthereto is added 10% hydrochloric acid (10 ml). The mixture is subjectedto catalytic hydrogenation using platinum oxide as a catalyst. After thereaction is completed, platinum oxide is removed by filtration, and thefiltrate is evaporated under reduced pressure to give2-n-propylhistamine hydrochloride (4.83 g).

(3) A mixture of the above compound (4.83 g), phthalic anhydride (3.04g), sodium acetate (6.10 g) and acetic acid (50 ml) is refluxed for 19hours. The mixture is evaporated under reduced pressure, and water isadded to the resulting residue. The mixture is neutralized with sodiumhydrogen carbonate, and extracted with chloroform. The extract is dried,and evaporated, and the resulting residue is purified by silica gelcolumn chromatography (solvent; chloroform/methanol=20:1) to give2-n-propyl-4(2-phthalimidethyl)imidazole (2.72 g).

m.p. 137°-139° C. NMR (CDCl₃) δ: 0.90 (3H, t), 3.95 (2H, t), 7.61-7.86(4H, m)

Reference Example 4

The compound obtained in Reference Example 3 is treated in the samemanner as in Example 1 to give2-n-propyl-4-(2-phthalimidethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazoleas foam.

NMR (CDCl₃) δ: 0.86 (3H, t), 4.82 (2H, s)

Oxalate

m.p. 112° C. (sintered)

Reference Example 5

To a mixture of the compound obtained in Reference Example 4 (4.11 g)and ethanol (100 ml) is added 10% hydrazine hydrate (2 ml), and themixture is stirred at room temperature for 5 hours. After the reactionis completed, chloroform is added to the reaction mixture, and themixture is washed, dried and evaporated to give crude2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(3.68 g) as an oil.

Reference Example 6

4-[2'-(t-Butoxycarbonylamino)ethyl]2-n-butylimidazole (3.0 g) and methyl4-bromomethylbiphenyl-2-carboxylate (3.75 g) are treated in the samemanner as in Example 1 to give2-n-butyl-4-(2-t-butoxycarbonylaminoethyl)-1-[2'-methoxycarbonylbiphenyl-4-yl]methylimidazole(2.65 g) as an oil.

EI-MS (m/z): 491 (M³⁰), 225 (base) NMR (CDCl₃) δ: 0.91 (3H, t), 3.66(3H, s), 5.02 (2H, s)

Reference Example 7

A mixture of the compound obtained in Reference Example 6, 10%hydrochloric acid (40 ml) and methanol (60 ml) is refluxed for one hour.After the reaction is complete, the mixture is evaporated to remove themethanol, and the aqueous layer is washed and concentrated to drynessunder reduced pressure. The resulting residue is subjected to azeotropicdistillation with dry toluene to give crude2-n-butyl-4-(2-aminoethyl)-1-(2'-methoxycarbonylbiphenyl-4-yl)methylimidazolehydrochloride.

Reference Example 8

(1) n-Butanamidine hydrochloride (5.0 g) and potassium carbonate (11.4g) are suspended in acetonitrile (100 ml), and the mixture is heated at80° C. to 90° C. To the mixture is added dropwise a solution of1-bromo-4-phthalimidbutan-2-one (10.0 g) in acetonitrile (200 ml) withstirring, and the mixture is heated at the same temperature for 1.5hour. The insoluble materials are removed by filtration, and thefiltrate is concentrated. The resulting residue is dissolved in ethylacetate, washed with water, dried over sodium sulfate, and evaporated.Fumaric acid is added to the residue, and the product is recrystallizedfrom ethanol/ether to give 2-n-propyl-4-(2-phthalimidethyl)imidazole 1/2fumarate (9.9 g).

m.p. 185°-187° C.

(2) The above fumarate (13.7 g) is suspended in ethyl acetate/water, andthereto is added sodium hydrogen carbonate (5.8 g) to give2-n-propyl-4-(2-phthalimidethyl)imidazole (9.24 g). To a solution of theproduct (9.24 g) and 4-(2'-cyanophenyl)benzyl bromide (9.3 g) intetrahydrofuran (150 ml) and dimethylformamide (10 ml) is added dropwisea solution of potassium t-butoxide (3.84 g) in tetrahydrofuran (50 ml)at 50° C. The mixture is allowed to warm to 20° C., and stirred for twohours. The reaction is quenched with aqueous ammonium chloride solution,and the mixture is extracted with ethyl acetate, and the ethyl acetatelayer is washed with water, and dried over sodium sulfate, andevaporated to give a colorless oily product (15.3 g). The product isdissolved in ethanol, and thereto is added oxalic acid, and the productis recrystallized from ethanol to give2-n-propyl-4-(2-phthalimidethyl)-1-(2'-cyanobiphenyl-4-yl)methylimidazoleoxalate (13.44 g).

m.p. 162°-166° C. NMR (DMSO-d₆) δ: 0.82 (3H, t), 2.60-3.10 (4H, m), 5.34(2H, s)

(3) A mixture of 2-n-propyl-4-(2-phthalimidethyl)-1-(2'-cyanobiphenyl-4-yl)methylimidazole (0.5 g) and tributyltin azide(0.70 g) is heated overnight at 110° C. To the reaction mixture is added8% hydrogen chloride ethanol solution (5 ml), and the solution isstirred for 30 minutes at room temperature, then evaporated. The residueis dissolved in water (30 ml), and the solution is washed with ether.The aqueous layer is neutralized with sodium hydrogen carbonate, andextracted with chloroform. The chloroform solution is dried, andevaporated. To the residue (575 mg) are added triphenylchloromethane(0.38 g), triethylamine (0.20 ml) and chloroform (5.0 ml). The solutionis stirred for two hours at room temperature, then washed with asaturated sodium hydrogen carbonate solution and brine, dried oversodium sulfate, and evaporated. To the residue is added oxalic acid(0.10 g), and the mixture is recrystallized from ethanol to give2-n-propyl-4-(2-phtalimidethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazoleoxalate (0.70 g).

m.p. 112° C. (sintered)

Reference Example 9

To a solution of 1-(diethoxy)methylimidazole (260 g) in tetrahydrofuran(5 liters) is added dropwise 1.6M solution of n-butyl lithium in hexane(1 liter) at -45° C. Thirty minutes thereafter, n-butyl iodide (294 g)is added dropwise to the mixture at the same temperature. The reactionmixture is stirred overnight at room temperature and then evaporated. Tothe residue is added ether (2 liters), and the solution is extractedwith 10% hydrochloric acid. The aqueous solution is basified with 10%sodium hydroxide solution, then evaporated with chloroform. The organiclayer is washed, dried and evaporated. To the crude product (204 g),triethylamine (170 g) and chloroform (2 liters) is added dropwise asolution of dimethylsulfamoyl chloride (200 g) in chloroform (200 ml)under ice-cooling. The mixture is stirred overnight at room temperature,washed with brine, dried, and evaporated. The crude product is purifiedby distillation to give 2-n-butyl-1-dimethylsulfamoylimidazole (249.4g).

b.p. 124° C. (1 mmHg)

Reference Example 10

1-(Diethoxy)methylimidazole and n-propyl lithium are treated in the samemanner as in Reference Example 9 to give2-n-propyl-1-dimethylsulfamoylimidazole.

b.p. 141°-143° C. (3 mmHg)

Reference Example 11

To a stirred solution of 2-ethylimidazole (100 g) and triethylamine (115g) in chloroform (800 ml) at 0° C. is added a solution ofdimethylsulfamoyl chloride (153 g) in chloroform (200 ml). The mixtureis stirred overnight at room temperature. Water (1.5 liter) is added tothe reaction mixture after which the organic layer is separated andconcentrated. The residue is dissolved in ethyl acetate (1 liter) andwashed with water, and then dried over sodium sulfate and concentrated.Distillation gives 1-dimethylsulfamoyl-2-ethylimidazole (182 g) as acolorless liquid.

b.p. 139°-142° C. (5 mmHg) NMR (CDCl₃) δ: 1.37 (3H, t), 2.89 (6H, s),6.94 (1H, d), 7.23 (1H, d)

Reference Example 12

To a stirred solution of the above product (53 g) in tetrahydrofuran (1liter) at -78° C. is added 1.6M solution of n-butyl lithium in hexane(185 ml). The solution is stirred at -78° C. for one hour, and theretois added a solution of 1-t-butoxycarbonylaziridine (52 g) intetrahydrofuran (300 ml), and further added thereto boron trifluorideetherate (147 g). The reaction mixture is stirred for another two hoursat -78° C. after which it is poured into an ice-cooled saturated aqueoussolution of potassium carbonate (2 liters). After evaporation of theremaining tetrahydrofuran, the aqueous layer is extracted with ethylacetate, washed with water and dried over sodium sulfate, and thenconcentrated. The residue is purified by silica gel columnchromatography (solvent; chloroform/methanol) to give1-dimethylsulfamoyl-2-ethyl-5-[2-(t-butoxycarbonylamino)ethylimidazole(67 g) as a yellow oil.

NMR (CDCl₃) δ: 1.35 (3H, t), 1.43 (9H, s), 2.87 (6H, s), 6.72 (1H, s)

Reference Example 13

A solution of the above product (67 g) in 10% hydrochloric acid (600 ml)is refluxed for two hours. The solvent is distilled off under reducedpressure and the resulting oily black residue is dissolved in aceticacid (300 ml). After addition of sodium acetate (62 g) and phthalicanhydride (34 g), the reaction mixture is refluxed overnight. Thereaction mixture is concentrated under reduced pressure and the residueis triturated in acetone (300 ml) to give the crude2-ethyl-4-(2-phthalimidethyl)imidazole (26 g) as a white powder. Thisproduct is used in the next reaction without further purification.

Reference Example 14

To a solution of the above product (6.56 g) and2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl bromide (16.3 g) intetrahydrofuran (100 ml) dimethylformamide (50 ml) at -60° C. is addedpotassium t-butoxide (3.01 g). The reaction mixture is allowed to slowlywarm to room temperature in 5 hours and then poured into brine (2liters), extracted with ethyl acenate, washed with brine and dried oversodium sulfate. After concentration, the residue is purified by silicagel column chromatography (solvent; hexane/ethyl acetate) to give2-ethyl-4-(2-phthalimidethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(10.69 g) as a white foam, characterized as its fumarate.

m.p. 173°-174° C. NMR (DMSO-d₆) δ: 0.92 (3H, t), 2.35 (2H, q), 2.73 (2H,t), 3.78 (2H, t), 4.99 (2H, s)

Reference Example 15

To a solution of the above product (10.69 g) in ethanol (150 ml) andtetrahydrofuran (90 ml) at 0° C. is added hydrazine hydrate (6.25 g).The reaction mixture is stirred overnight at room temperature, filteredthrough a celite pad and evaporated. The residue is treated with 0.5Nsodium hydroxide solution (300 ml) and extracted with chloroform. Theorganic layer is dried over sodium sulfate and concentrated to give thecrude2-ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(7.48 g) as a foam. This product is used without further purification.

Reference Example 16

To a solution of 2-ethyl-4-(2-phthalimidethyl)imidazole (9.00 g) and2'-(t-butoxycarbonyl)biphenyl-4-yl-methyl bromide (13.93 g) intetrahydrofuran (150 ml) and dimethylformamide (100 ml) at -60° C. isadded potassium t-butoxide (4.12 g). The reaction mixture is allowed toslowly warm to room temperature in four hours and then poured into water(100 ml). Tetrahydrofuran is removed under reduced pressure and theaqueous layer is extracted with ethyl acetate. The organic layer iswashed with brine, dried over sodium sulfate and then evaporated to givean oily residue. Purification by silica gel column chromatography(solvent; hexane/ethyl acetate) gives2-ethyl-4-(2-phthalimidethyl)-1-[2'-(t-butylcarbonyl)biphenyl-4-yl]methylimidazole(9.39 g) as an oil.

NMR (CDCl₃) δ: 1.20 (3H, t), 1.25 (9H, s), 5.02 (2H, s), 6.64 (1H, s)

Reference Example 17

The compound obtained in Reference Example 16 is treated in the samemanner as in Reference Example 15 to give2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole.

FAB-MS (m/z): 406 (M+1), 211 (base) NMR (CDCl₃) δ: 1.26 (9H, s), 1.29(3H, t), 5.06 (2H, s), 6.60 (1H, s)

Reference Example 18

2-n-Butyl-1-dimethylsulfamoylimidazole (46.0 g) is treated in the samemanner as in Reference Example 12 to give2-n-butyl-1-dimethylsulfamoyl-5-[2'-(t-butoxycarbonyl)aminoethyl]imidazole(69 g) as an oil.

NMR (CDCl₃) δ: 0.95 (3H, t), 1.43 (9H, s), 2.86 (6H, s)

Reference Example 19

2-n-Butyl-1-dimethylsulfamoyl-5-[2'-(t-butoxycarbonyl)aminoethyl]imidazole(115.3 g) is treated in the same manner as in Reference Example 15 togive 2-n-butyl-4-(2-phthalimidethyl)imidazole (64 g).

m.p. 114°-117° C. NMR (CDCl₃) δ: 0.88 (3H, t), 2.66 (2H, t), 2.97 (2H,t), 3.95 (2H, t), 6.67 (1H, s)

Reference Example 20

The compound obtained in Reference Example 19 is treated in the samemanner as in Reference Example 14 to give2-n-butyl-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4-(2-phthalimidethyl)imidazole.

NMR (CDCl₃) δ: 0.84 (3H, t), 4.81 (2H, s)

Reference Example 21

A mixture of2-n-butyl-4-(2-phthalimidethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(96.0 g), hydrazine hydrate (44.7 g) and ethanol (1.3 liter) is stirredovernight at room temperature, then filtered through a celite pad andevaporated. The residue is treated with 5% sodium hydroxide solution(200 ml) and extracted with chloroform. The organic layer is dried andconcentrated to give the crude2-n-butyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole(84.0 g). To a solution of the above product (84.0 g) in methanol isadded a 24% hydrogen chloride methanol solution (200 ml), and themixture is evaporated. To the residue is added water (2 liters), and themixture is washed with ether. The aqueous layer is concentrated to give2-n-butyl-4-(2-aminoethyl)-1-[2'-(1-tetrazol-5-yl)biphenyl-4-yl]methylimidazoledihydrochloride (52.8 g) as a foam.

NMR (DMSO-d₆) δ: 0.83 (3H, t), 2.92 (2H, t), 5.41 (2H, s)

Reference Example 22

2-n-Propyl-1-dimethylsulfamoylimidazole (20.0 g) is treated in the samemanner as in Reference Example 12 to give2-n-propyl-1-dimethylsulfamoyl-5-(2-t-butoxycarbonylaminoethyl)imidazole(24.4 g) as an oil. NMR (CDCl₃) δ: 1.01 (3H, t), 1.43 (9H, s), 2.86 (6H,s), 6.71 (1H, s)

Reference Example 23

The compound obtained in Reference Example 22 is treated in the samemanner as in Reference Example 15 to give2-n-propyl-4-(2-phthalimidethyl)imidazole.

m.p. 137°-139° C. NMR (CDCl₃) δ: 0.90 (3H, t), 3.95 (2H, t), 6.68 (1H,s)

Reference Example 24

To a mixture of 2-n-propyl-4-(2-phthalimidethyl)imidazole (10.0 g),2'-(t-butoxycarbonyl)biphenyl-4-ylmethyl bromide (13.5 g),tetrahydrofuran (150 ml) and dimethylformamide (15 ml) is added asolution of potassium t-butoxide (4.16 g) in tetrahydrofuran (40 ml) at-60° C. The mixture is allowed to warm to room temperature, and thenquenched with water. The mixture is extracted with ethyl acetate, andthe organic layer is washed, dried and evaporated. The crude product iscrystallized with oxalic acid from ethanol/ether to give2-n-propyl-4-(2-phthalimidethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazoleoxalate (15.6 g).

m.p. 128-131° C. NMR (DMSO-d₆) δ: 0.84 (3H, t), 1.19 (9H, s), 5.30 (2H,s)

Reference Example 25

To a mixture of2-n-propyl-4-(2-phthalimidethyl)-1-[2'-(tert-butoxycarbonyl)bipheyl-4-yl]methylimidazole(15.5 g) and ethanol (150 ml) is added hydrazine hydrate (8.45 g) atroom temperature. The mixture is stirred overnight, and the precipitateis removed by filtration. The filtrate is evaporated, and the resultingresidue is dissolved in chloroform and washed with 3% sodium hydroxidesolution and brine. The organic layer is dried and evaporated to givethe crude2-n-propyl-4-aminoethyl-1-[2'-(tert-butoxycarbonyl)biphenyl-4-yl]methylimidazole(10.0 g). This compound is used in the next step without furtherpurification.

Effects of the Invention

The imidazopyridine derivatives [I] of the present invention andpharmaceutically acceptable salts thereof show excellent angiotensin IIantagonistic activities and are useful in the prophylaxis and/ortreatment of hypertension. For example, when hypotensive activity wasexamined by using spontaneously hypertensive rats orally administered ata dose of 3 mg/kg of the desired compounds [I] of the present invention,significant hypotensive activity was observed as compared with that ofthe control group of rats to which purified water is orallyadministered. Moreover, the compounds [I] of the present invention andpharmaceutically acceptable salts thereof show low toxicity, and hence,they show high safety as a medicament.

What is claimed is:
 1. An imidazopyridine derivative of the formula (I):##STR43## wherein R¹ is a lower alkyl group; R² is a hydrogen atom, alower alkylsulfonyl group or a group of the formula ##STR44## which Z isan oxygen atom or two hydrogen atoms, and R⁰ is i) a lower alkyl groupwhich may optionally be substituted by 1 to 2 groups selected fromphenyl, halogenophenyl, carboxyl, lower alkoxycarbonyl, cyano,benzyloxycarbonyl, lower alkylthio, lower alkylcarbonylamino, benzoyland lower alkylcarbonyl, ii) a lower alkoxy group, iii) a phenyl group,iv) a hydrogen atom, v) a di (lower alkyl)amino group or vi) a loweralkenyl group;R³ is carboxyl group or a lower alkoxy-carbonyl group; andRing A is a phenyl group substituted with a group selected from aprotected tetrazolyl group, unprotected tetrazol group, carboxyl groupand lower alkoxycarbonyl group, provided that, when R² is a group of theformula ##STR45## in which Z is an oxygen atom and R⁰ is lower alkylgroup, Ring A is a phenyl group substituted with a group selected fromcarboxyl and alkoxcarbonyl, or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1, wherein the protectedtetrazolyl group is a tetrazolyl group protected by a group selectedfrom a trityl group, a tri-lower alkylsilyl group, a cyano-lower alkylgroup and a lower alkoxybenzyl group.
 3. The compound according to claim1, wherein R² is hydrogen or a group of the formula ##STR46## in which Zis oxygen atom, and R⁰ is i) a lower alkyl group or a lower alkyl groupsubstituted with a carboxyl group, ii) a lower alkoxy group, or iii) aphenyl group; and Ring A is a phenyl group substituted with a groupselected from tetrazolyl, carboxyl and lower alkoxycarbonyl.
 4. Thecompound according to claim 3, wherein R² is hydrogen atom, a loweralkylcarbonyl group, a carboxy-lower alkylcarbonyl group or aphenylcarbonyl group.
 5. The compound according to claim 3 or 4, whereinR³ is a carboxyl group.
 6. The compound according to claim 5, wherein R²is a lower alkylcarbonyl group; and Ring A is a carboxyl-substitutedphenyl group.
 7. The compound according to claim 5, wherein Ring A is atetrazoyl-substituted phenyl group.
 8. A pharmaceutical compositionwhich comprises a therapeutically effective amount of the compound asset forth in claim 5 in admixture with a conventional pharmaceuticallyacceptable carrier or diluent.
 9. A method for the prophylaxis ortreatment of hypertension which comprises administering to awarm-blooded animal in need of said prophylaxis or treatment atherapeutically effective amount of the compound as set forth in claim5.
 10. A pharmaceutical composition which comprises a therapeuticallyeffective amount of the compound as set forth in claim 3 in admixturewith a conventional pharmaceutically acceptable carrier or diluent. 11.A method for the prophylaxis or treatment of hypertension whichcomprises administering to a warm-blooded animal in need of saidprophylaxis or treatment a therapeutically effective amount of thecompound as set forth in claim
 3. 12. A pharmaceutical composition whichcomprises a therapeutically effective amount of the compound as setforth in claim 1 in admixture with a conventional pharmaceuticallyacceptable carrier or diluent.
 13. A method for the prophylaxis ortreatment of hypertension which comprises administering to awarm-blooded animal in need of said prophylaxis or treatment atherapeutically effective amount of the compound as set forth inclaim
 1. 14. [2-n-Propyl-5-acetyl-3-(2'- (1H-tetrazol-5yl)biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo (4,5-c)-pyridine-4carboxylic]2-n-Propyl-5-acetyl-3-(2'-carboxy-biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo(4, 5-c)-pyridine-4 -carboxylic acid or a pharmaceutically acceptablesalt thereof. 15.[2-n-Butyl-5-acetyl-3-(2'-1H-tetrazol-5-yl)biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo(4,5-c)-pyridine-4-carboxylic]2-n-Butyl-5-acetyl-3(2'-carboxy-biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo(4,5-c)-pyridine-4-carboxylicacid or a pharmaceutically acceptable salt thereof. 16.[2-n-Butyl-5-propionyl-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo(4,5,-c)-pyridine-4-carboxylic]2-n-Butyl-5-(3-carboxypropionyl)3-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-4,5,6,7-tetrahydroimidazo(4,5-c)-pyridine-4-carboxylic acid and a pharmaceutically acceptablesalt thereof.